21-halosteroids



. steroids United States Patent 'ce ZI-HALDSTEROIDS Eugene J. Agnello and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer 8; (10., Inc., New York, N.Y., a corporation of Delaware No Drawing. Application April 25, 1957 Serial No. 654,984

6 Claims. (Cl. 167-6 This invention is concerned with 21-fluoro derivatives of A -corticosteroids and N -corticosteroids. These novel compounds are valuable synthetic hormones which invention comprise compounds selected from the class consisting of:

wherein R is chosen from the group consisting of keto and fl-hydroxyl, and X is chosen from the group consisting of a-hydrogen, a-fluorine, ot-chlorine, u-bromine and R on

' and a-iodine. There are also included in this invention pharmaceutical compositions comprising a compound as described above together with pharmaceutically acceptable carriers.

-In accordance with the present invention, it has been unexpectedly discovered that the 21-fluoro-A -corticoand 21-fluoro-A -corticosteroids described herein produce in full measure all the beneficial effects of cortisone without any serious. side effects; in partic- 2,907,694 Patented Oct. 6,

21-hydroxy-A -corticosteroids with a compound chosen from the group consisting of methanesulfonyl chloride,

, ethanesulfonyl chloride, benzenesulfonyl chloride and ptoluenesulfonyl chloride; treating the resulting 21-ester with a compound chosen from the group consisting of alkali metal iodides and bromides; and then subsequently contacting the resulting 21-iodo or -bromo compound with an inorganic fluoride, preferably sodium fluoride, potassium fluoride, cuprous fluoride, silver fluoride or mercurous fluoride.

A preferred embodiment of the foregoing process is carried out by contacting the 2l-hydroxy compound in an organic base solvent, such as trimethylamine, triethylamine, diethylaniline and pyridine, with p-toluene sulfonyl chloride dissolved in a chlorinated hydrocarbon solvent, such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride and tetrachlorethylene at a temperature in the range from about 20 to about +10 C. for a time period preferably in the range of from about 0.5 to 4 hours; treating the resulting 21- tosyl intermediate in an inert neutral, polar organic solvent, such as acetone or lower alkanols, with an alkali metal iodide, such as sodium iodide, potassium iodide, etc.; and then subsequently contacting the resulting 21-iodo compound in an inert polar organic solvent, such as acetone or acetonitrile, with silver fluoride, preferably in the range of about 20 to about C.

The first step of this process involves the formation of the p-toluenesulfonic acid ester (the tosylate). As an illustration, the 21-tosylates are most desirably'prepared in pure condition and in good yields by dissolving the corresponding 21-hydroxy-A -corticosteroid in anhydrous pyridine or diethylaniline at room tempera- .1 mains in solution, allowing the mixture to stand in the the inflammatory manifestations of rheumatoid arthritis,

metabolic studies have shown these 21-fluoro-A -corticosteroids not vto cause retention of sodium. Furthermore, they cause little or no loss of nitrogen, phosphorus, calciumand potassium from the system of the patient as noted with other forms of cortical steroid therapy.

1 In accordance with the process of the present invention, suitable starting materials for the synthesis of the compounds described herein include A -pregnadienell[3,l7a,2l-trihydroxy-3,20-dione, A -pregnadiene-l7a, 2l-dihydroxy-3,l1,20-trione, A pregnatriene-17u,2ldihydroxy-3, l1,20-trione and their 9a-halo derivatives, such as t-fluoro, zrchloro, u-bromo and wiodo. These compounds 6311? be prepared from readily available organic starting materials by well-known synthetic and biochemical procedures as previously described in the this reaction, pyridine not only acts as a solvent but also serves to accelerate the reaction rate as it removes the hydrogen chloride by-product due to salt formation; this in turn, shifts the equilibrium in favor of the tosylate.

The second step of this process is most preferably carried out by treating the 21-tosyl intermediate with at least an equimolar amount of sodium iodide in acetone or a lower alkanol, affording the corresponding 2l-iodo- A -corticosteroids. This reaction is most conveniently carried out at the reflux temperature, but it may be performed at any temperature in the range of about 20 to about 100 (3., although most preferably in the range of from about 40 to about C. These 21-iodosteroids, are pale-yellow crystalline substances which are very stable; they retain this light'color even after storage for a about six months without exposure to light.

cess of a 50% aqueous solution of silver fluoride at a temperature preferably in the range :from about 20 to 7 about 50 C. Upon termination of the reaction, a precipitate of silver iodide separates out, the 21-fluorosteroid remaining in solution; evaporation of the filtrate in vacuo easily affords the desired product.

The therapeutically active compounds of this invention may be administered either alone or in combination with an acceptable pharmaceutical carrier. Selection of the latter is determined by the preferred route of administration, the solubility of the compound and standard pharmaceutical practices. In general, the dosage of these compounds is approximately of the same order of magnitude as the dosage of cortisone, hydrocortisone and prednisone, in place of which they are used to treat similar types of pathological conditions. However, in view of their great adrenocortical activity, it is sometimes possible to use dosages of these compounds which are lower than those employed with prednisone.

For purposes of oral administration, the compound may be administered in the form of tablets containing excipients such as starch or milk sugar; aqueous suspenstandard pharmaceutical practices.

This invention is further illustrated by the following examples, which are not to be considered as imposing any limitation thereon.

Example I To a solution of 1 g. of A -pregnadiene-11 3,I7a,21- trihydroxy-3,20-dione in 10 ml. of anhydrous pyridine placed in a Dry Ice-acetone bath was added a solution of 600 mg. of anhydrous tosyl chloride in 67ml. of dry methylene chloride (this solution had been cooled to such an extent that the tosyl chloride just remained in solution) with constant agitation. After the addition was complete, agitation was continued while the reaction mixture was allowed to stand in the bath for 2 hours at -18 C. and subsequently at +2 C. for about 18 hours. The solution was then diluted with an equal volume of ether and washed twice with water. After drying over anhydrous sodium sulfate, the filtered solution was evaporated in vacuo to dryness. The residue so obtained was dissolved in ml. of methanol and filtered immediately; the filtrate on standing deposited crystals of 21- tos'yl-A -pregnadiene-11B,l7a,2l-trihydroxy 3,20-dione which were then filtered and air dried to constant tem perature.

To a solution of 1 g. of this intermediate in 5 ml. of

acetone was added a solution of 1 g. of sodium iodide Example 11 I To asolution of 2I-iodO-M -pregnadiene-I1;3,17a- 1i.

I trione, respectively.

, 4 hydroxy-3,20-dione dissolved in moist acetonitrile was added a slight excess of a 50% aqueous solution of silver fluoride at 30 to 40 C. A precipitate of silver iodide separated immediately and was removed by means of filtration, while the fluorosteroid remained in solution. Upon evaporation of the solvent in vacuo, the desired material separated out. It was then filtered, Washed with water and air-dried; recrystallization of this material from methanol-chloroform aflorded pure 21-fluoro- A -pregnadiene-l15,17a-dihydroxy-3,20-dione. In an analogous manner, 2l-bromo-A -pregnadiene-1113,170:- dihydroxy-3,20-dione afiorded the same product.

In a similar manner, the 9a-bromo and 9a-iodo derivatives of these compounds were prepared. Furthermore, these same reactions have also been carried out by employing either sodium fluoride, potassium fluoride,

cuprous fluoride or mercurous fluoride in place of the silver fluoride.

Example III A pregnadiene l7oc,2l dihydroxy g 3,11,20 trione was subjected to the series of reactions as described in Examples I and II. The corresponding 2l-tosyl and 21-iodo intermediates were obtained, as well as the final product, 2l-fluoro-A -pregnadiene-l7a-hydroxy-3,l1,20- trione.

In a similar manner, the 9a-chloro, 9u-bromo and 9aiodo derivatives of these compounds were prepared;

Example IV Example V A11416 pregnatriene 11B,17a,21 trihydroxy 3,20 dione and A -pregnatriene-l7a,21-dihydroxy-3,11,20- trione were both subjected to the series of reactions described in Examples I and II. In each case, the corresponding 2l-tosyl and 21-iodo or -bromo intermediates were obtained, as well as the desired final products, 21- fluoro A pregnatriene 113,21 dihydroxy 3,20 dione and 21-fluoro-A -pregnatriene-l7a-hydroxy-3, 11,20-trione, respectively. 1

In an analogous manner the Qua-fluoro derivatives of these A -prcgnatrienes were prepared, that is to say, the final products obtained were 9a,2l-difluoro-A pregnatriene-11B,17a-dihydroxy-3,20-dione and 905,21-difluoro A pregnatriene 17a hydroxy 3,11,20 In a similar manner, the 9a-chloro, 9a-bromo and 9a-iodo derivatives were also prepared,

What is claimed is:

1. A compound selected from the class consisting of:

and

ptmnd 'as claimed in claim 1 together with a pharmaceutically acceptable carrier.

3. 900,21 difluoro A pregnatriene 1119,1700

References Cited in the file of this patent UNITED STATES PATENTS -mfi- $32 323 gig 4. 900,21 difluoro A pregnadiene 113,170: 5 7 dihydmxyagodiom I OTHER REFERENCES 5. 21 fluoro A1045 pregnatriene 115,170: dihy- Tannahauser et al.: J.A.C.S., June 5, 1956, pages droxy-3,20-dione. 2658-2659.

6. 21 fluoro A pregnadiene 115,1700 dihy- Herz et aL: J.A.C.S., September 20, 1956, pages droxy-3,20-dione. 10 4812-4814. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF:
 2. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND AS CLAIMED IN CLAIM 1 TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER. 